Clostridium difficile (C. difficile) causes debilitating antibiotic associated diarrhea in hospital patients and is a pathogen in which alternatives to antibiotic therapies are necessitated. C. difficile infections (CDI) are dependent on the production of the intracellular toxins, including TcdB, whose sequence and toxicity varies among different strains of C. difficile. The most recent reports estimate nearly 500,000 cases of C. difficile infection in the US every year, with total deaths approaching 30,000 annually. Treatment options are very expensive and obviously are not ideal or even very effective given the steady rise in the number and severity of C. difficile infections. There are a number of anti-toxin technologies available or proposed for treating C. difficile infections. These include (1) humanized monoclonal antibodies against TcdA and TcdB (from Merck, in Phase III trials) which are effective against multiple ribotypes of C. difficile and reduce rates of C. difficile recurrence (however, these are likely to be cost-prohibitive except in severe cases), (2) fecal microbiota transplantation (FMT), which is a cost effective treatment for patients with recurring C. difficile disease, but is not used to treat primary infection, (3) toxoid vaccines of TcdB and TcdA toxins, which are in phase-III clinical trials at Sanofi (e.g., Cdiffense trial), and which may be highly effective, but will only be used on a specific group of individuals and not in treatments for active disease or community-acquired C. difficile, and (4) atoxigenic C. difficile which has been used to compete with toxic strains of C. difficile in the intestinal tract.
Currently there are no peptide-based inhibitors approved for treatment of bacterial toxins, including C. difficile toxins. However, such a drug could reach a large patient market, as noted above. In 2014 there were 500-600 peptides in preclinical trials, 40 in phase-I trials, 74 in phase-II trials, and 14 in phase-III trials. These trials included both use of peptides as vaccines and for treatment of acute conditions. About 100 therapeutic peptides, including diagnostics are on the market in the US, Europe and Japan. Examples of major peptides in this market are Goserelin/Zoladex and Leuroprolide used to treat breast and prostate cancer and Octreotide used to treat various tumors. Annual sales are between $US 1.2 and 1.4 billion. Thus there is a growing precedent for considering peptides as therapeutics. A therapy that targets TcdB along with variant forms of this toxin would be an ideal approach to counter CDI and could serve as alternative to antibiotics. It is to such peptide-based therapeutics for the treatment of CDIs that the present disclosure is directed.